Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus.
OBJECTIVE
Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts.


METHODS
The goal of this double-masked, placebo-controlled trial in type-2 diabetes was to assess the effect of the PKC beta-specific inhibitor, ruboxistaurin (32 mg/day for 6 weeks) on ultrasound assessed brachial artery flow mediated dilatation (FMD), a surrogate of macro vascular endothelial function, and urinary isoprostanes, indices of oxidant stress.


RESULTS
Compared to placebo, ruboxistaurin tended to improve FMD (difference in 6-week change in FMD, mean +/- SD millimeter) at one (0.13 +/- 0.26 mm, p = 0.08) and 5 min (0.12 +/- 0.21 mm, p = 0.02) after cuff deflation, but had no effect on nitroglycerin-mediated dilatation or urinary isoprostanes.


CONCLUSIONS
This proof of concept trial is the first to suggest that specific inhibition of PKC beta may improve macro vascular endothelial function in type-2 diabetes. Larger trials including clinical endpoints are warranted to determine the potential efficacy of PKC beta inhibition in reducing atherosclerotic cardiovascular complications in diabetes mellitus.
Mehta
Nehal N
NN
Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA.
Sheetz
Matthew
M
Price
Karen
K
Comiskey
Lynn
L
Amrutia
Shirish
S
Iqbal
Nayyar
N
Mohler
Emile R
ER
Reilly
Muredach P
MP
D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C